PROJECT SUMMARY Influenza (flu) infection is a leading cause of death in the elderly. Additionally, and importantly, it is a common yet under-recognized contributor to excess morbidity, disability and loss of independence in the elderly. We recently published evidence of the first known pathophysiological link between flu infection and declining mobility performance utilizing a murine model. Despite that active flu infection is localized to the lungs, there are clear functional decrements and molecular alterations in the muscle with upregulation of muscle inflammation and atrophy genes and downregulation of positive regulators of muscle growth. Importantly, the impact of flu infection on these molecular changes and overall functional declines is more pronounced and prolonged with aging. Our primary goal in this R21 proposal is to identify specific mechanisms linking pulmonary flu infection to declines in muscle health and functional ability. Since our data does not support direct viral infection of skeletal muscle, we believe systemic factors are at the root of flu-induced muscle atrophy. Thus, infections that generate a systemic response comparable to flu would hypothetically also contribute to muscle loss with aging. Thus, this proposal will delve into mechanisms behind not only flu-induced muscle atrophy, but the underlying mechanisms of other inflammation and/or infection-induced myopathy and disability with aging. To identify potential mechanisms behind flu-induced muscle atrophy, we will employ an unbiased systems-based approach to examine the relationship between immune responses, flu-induced inflammation, skeletal muscle tissue morphology, muscle function, and full muscle transcriptome. Implicated factors and pathways will be verified utilizing in vitro myoblast and myotube cultures and in vivo serum and/or cytokine/chemokine injections. The overarching scientific premise of this proposal is based on our published study that demonstrated increased muscle atrophy during flu infection with aging. We believe that lingering systemic inflammation in aged individuals during flu infection and increased muscle sensitivity to this inflammation contributes to increased muscle-localized inflammation, cellular infiltration, and muscle atrophy. Our integrated approach will test this hypothesis, while also generating additional unbiased hypotheses based on transcriptomics and statistical modeling to determine the driving mechanism behind flu-induced muscle atrophy. Understanding mechanisms responsible will guide preventative and therapeutic measures. Furthermore, this study has significant potential to discover high impact translational findings that will improve care for flu-infected elderly and help them maintain their independence later in life.